16-Methylene steroids are well known chemically in the estrone (aromatic A ring) series, see U.S. Pat. No. 3,257,429; in the corticoid series, see U.S. Pat. Nos. 3,157,679, 3,878,228, 3,354,184, 3,493,558 and 3,376,294; in the progesterone series, see U.S. Pat. Nos. 3,168,537, 3,157,679, 3,284,476 and 3,359,287; and in the androstane series, see U.S. Pat. Nos. 3,641,069 and 3,300,521.
Pharmacologically, the 16-methylene steroids are known to be useful as anti-inflammatory agents, see U.S. Pat. Nos. 3,641,069, 3,878,228 and 3,359,287; as progestational agents, see U.S. Pat. Nos. 3,157,679, 3,168,537, 3,284,476, 3,359,287 and 3,493,558; as estrogen hormonal agents, see U.S. Pat. Nos. 3,257,429 and 3,284,476; and as intermediates, see U.S. Pat. Nos. 3,300,521 and 3,354,184.
While there is more than one process to produce 16-methylene steroids, the most common process is the transformation of a 16-unsaturated-16-methyl steroid to the corresponding 16-methyl-16.alpha.,17.alpha.-epoxide followed by conversion to the corresponding 17.alpha.-hydroxy-16-methylene steroid, see U.S. Pat. Nos. 3,168,537, 3,354,184, 3,539,287, 3,493,558, 3,376,294 and 3,284,476. In addition, there is a process for the conversion of 17-keto steroids (I) to the corresponding 16-methylene steroid (III) by reacting the 17-keto steroid with formaldehyde (paraformaldehyde) and an amine followed by elimination of the amine, see U.S. Pat. Nos. 3,704,253 and 3,275,666. The process of the present invention first selectively activates the C.sub.16 position before reaction with formaldehyde and a base.
Y. Ueno et al. in Tetrahedron Letters 3753 (1978) described a process for reacting monosubstituted active methylene compounds (.beta.-ketoesters) with paraformaldehyde and base to produce .alpha.-methylenated esters. When cyclopentanone was the ketone portion of the .beta.-keto ester, .alpha.-methylenation occurred; however the yield was only 53%, and, more importantly, the product was not an .alpha.-methylenated cyclopentanone because ring opening occurred forming a substituted pentanoic acid.
Y. Ueno et al. in Chemistry Letters 47 (1979) applied the same method to .alpha.-monosubstituted .beta.-benzoylsulfones and obtained .alpha.-methylenated sulfones.
Processes are known for the production of various substituted 16-methylene steroids, see U.S. Pat. Nos. 3,641,069 and 3,376,294 (6-fluoro), 3,878,228 (9-fluoro), 3,157,679 (6.alpha.-methyl), and 3,300,521 (7-methyl).
Hungarian patent 019,495 discloses a process for transforming a 16-substituted (16-alkoxalyl) steroid to the corresponding 16-methylene steroid in 80-90% yield by reaction with aqueous formaldehyde in the presence of a nitrogen containing organic base such as triethylamine or pyridine which was used as the solvent.
P. DeRuggieri et al. in Gazetter Chim. Ital. 91, 672 (1961) described a procedure to transform a 17-keto steroid to the corresponding 16-methylene steroid by utilizing a Mannich reaction, not a 16-(alkyloxalyl) intermediate. DeRuggieri does produce a 16-(ethyloxalyl)-17-keto steroid intermediate but does not convert it to a 16-methylene steroid but rather forms a 16-methyl-16-(ethyloxalyl)-17-keto steroid intermediate which is transformed to a 16.beta.-methyl steroid, not a 16-methylene steroid.